With every formulation has its own advantage and limitation SEDDS or self-emulsifying oil formulations (SEOF) SEDDSs are mixtures of oils and surfactants, ideally isotropic and sometimes containing cosolvents, which emulsify spontaneously to produce fine oil-in-water emulsions when introduced into an aqueous phase under gentle agitation.

Self-emulsifying formulations spread readily in the gastrointestinal (GI) tract, where the digestive motility of the stomach and intestine provide the agitation required for self-emulsification in vivo in the lumen of the gut.¹¹ This spontaneous formation of an emulsion in the gastrointestinal tract liberates the drug in a solubilized form, and the small size of the formed droplet provides a large interfacial surface area for drug absorption¹².Apart from solubilization, the presence of lipid in the formulation further helps improve bioavailability by affecting the drug absorption. Selection of a suitable self emulsifying formulation depends upon the assessment of (I) the solubility of the drug in various components(II) the area of the self-emulsifying region as obtained in the phase diagram, and (III) the droplet size distribution of the resultant emulsion following self-emulsification.

COMPOSITION OF SEDDS:

SEDDS belong to lipid-based formulations. Lipid formulations can be oils, surfactant dispersions, emulsions, SEDDS, solid lipid nanoparticles and liposomes. SEDDS are isotropic mixtures of drug, oil/lipid, surfactant, and/ or cosurfactant, which form fine emulsion/lipid droplets, ranging in size from approximately 100 nm (SEDDS) to less than 50 nm for self-nanoemulsifying drug delivery systems (SNEDDS), on dilution with physiological fluid. The drug, therefore, remains in solution of the gut, avoiding the dissolution step that frequently limits the absorption rate of hydrophobic drugs from the crystalline state.¹³ (Table 1)

Table 1: Represent Physiochemical properties and main fatty acid composition of labrafil oil.¹⁵

OIL	MAIN FATTY ACID (%)	PEG GROUP	HLB	WATER SOLUBILITY AT 20 C
Labrasol	Caprylic (C8)	PEG 400	14	Soluble
	50%
	Capripic (C10)
	20% - 50%
Labrafac	Caprylic (C8)	PEG 200	10	Dispersible
CM10	50%
	Capripic (C10)
	50%
Labrafil WL	Oleic (C80) 24%-34%	PEG 400	6	Dispersible
2609 BS	Lenoleic (C80)
	53%-63%

I-Oils. Oils can solubilize the hydrophobic drug in a specific amount. It is the most important excipient because it can facilitate self-emulsification and increase the fraction of hydrophobic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract. Long-chain triglyceride and medium-chain triglyceride oils with different degrees of saturation have been used in the preparation of SEDDS. Modified or hydrolyzed vegetable oils have contributed widely to the success of SEDDS owing to their formulation and physiological advantages. Novel semisynthetic medium-chain triglyceride oils have surfactant properties and are widely replacing the regular medium- chain triglyceride.¹⁴

II- Surfactant. The most widely recommended surfactants are non-ionic surfactants with a relatively high hydrophilic–lipophilic balance (HLB) value. The surfactant concentration ranges between 30% and 60% (w/w) in order to form stable SEDDS¹⁶ Surfactants have a high HLB and hydrophilicity, which assists the immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous media. Surfactants are amphiphilic in nature and they can dissolve or solubilize relatively high amounts of hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and for prolonged existence of drug molecules.

III-Cosolvents/Cosarfactant: high surfactant concentrations ( more than 30% w/w) are needed in order to produce an effective self-emulsifying system. Organic solvents, suitable for oral administration (ethanol, propylene glycol (PG), polyethylene glycol (PEG), etc.) may help to dissolve large amounts of either the hydrophilic surfactant or the drug in the lipid base. These solvents sometimes play the role of the cosurfactant in the microemulsion systems.

MECHANISM OF SELF-EMULSIFICATION:

The process by which self-emulsification takes place is not yet well understood. However, according to Reiss¹⁷, self-emulsification occurs when the entropy change that favours dispersion is greater than the energy required to increase the surface area of the dispersion. In addition, the free energy of a conventional emulsion formation is a direct function of the energy required to create a new surface between the two phase and can be described by equation given below

Where, G is the free energy associated with the process (ignoring the free energy of mixing), N is the number of droplets of radius, r, and s represents the interfacial energy. With time, the two phases of the emulsion will tend to separate, in order to reduce the interfacial area, and subsequently, the free energy of the systems. Therefore, the emulsions resulting from aqueous dilution are stabilized by conventional emulsifying agents, which form a monolayer around the emulsion droplets, and hence, reduce the interfacial energy, as well as providing a barrier to coalescence. In the case of self-emulsifying systems, the free energy required to form the emulsion is either very low and positive, or negative (then, the emulsification process occurs spontaneously). For emulsification to occur, it is necessary for the interfacial structure to have no resistance to surface shearin¹⁸.(Table 2)

The high stability of these self-emulsified systems to coalescence is considered to be due to the liquid crystal interface surrounding the oil droplets. The involvement of the liquid crystal phase in the emulsion formation process was extensively studied by Pouton et al.^19-22 Later, Craig et al. used the combination of particle size analysis and low frequency dielectric spectroscopy (LFDS) to examine the self-emulsifying properties of a series of Imwitor 742 (a mixture of mono- and diglycerides of capric and caprylic acids)/Tween 80 systems.^23,24.

Table 2: Example of surfactants, co-surfactant, and co-solvent used in commercial formulations

Excipient Name (commercial name)	Example of commercial products in which it has been used
Surfactants/co-surfactants
Polysorbate 20 (Tween 20)	Targetin soft gelatin capsule
Polysorbate 80 (Tween 80)	Gengraf hard gelatin capsule
Sorbitan monooleate (Span 80)	Gengraf hard gelatin capsule
Polyoxy-35-castor oil (Cremophor RH40)	Gengraf hard gelatin capsule, Ritonavir soft gelatin capsule

Polyoxy-40 hydrogenated castor oil (Cremophor RH40)	Nerol Soft gelatin capsule, Ritonavir oral solution
Co-solvents
Ethanol	Nerol soft gelatin Capsule, Nerol Oral
	Solution, Gengraf hard gelatin Capsule,
	Sandimmune soft gelatin Capsule,
	Sandimmune oral solution
Glycerin	Nerol soft gelatin Capsule, Sandimmune soft
	gelatin Capsules
Polypylene glycol	Nerol soft gelatin Capsule, Nerol Oral
	solution Camprenesoft gelatin capsule,
Polyethylene glycol	Agenerase soft Capsule, agenerase oral solution
Lipid ingredients
Corn oilmono, di, tri-glycerides	Nerol soft gelatin Capsule, Nerol Oral Solution
DL-alpha - Tocopherol	Nerol Oral Solution, Fortavase soft gelatin capsule
Fractionatd triglyceride of coconut oil	Rocoltrol soft gelatin capsule, Hectorl soft
(medium-chain triglyceride)	gelatin capsule
Fractionatd triglyceride of palm seed oil	Rocatrol oral solution
(medium-chain triglyceride)
Corn oil	Sandimmune soft gelatin capsule, Depakene capsule
Olive oil	Sandimmune oral solution
Oleic acid	Ritonaivr soft gelatin capsule, Norvir soft
	gelatin capsule
Sesame oil	Marinol soft gelatin capsule
Hydrogenated soyabean oil	Accure soft gelatin capslue, Vesanoid soft gelatin capsule
Beeswax	Vesanoid soft gelatin capsule
Peanut oil	Prometrium soft gelatin capsule
Soyabean oil	Accurate soft gelatin capsule

Biopharmaceutical aspects regarding SEDDS:

The ability of lipids and/or food to enhance the bioavailability of poorly water-soluble drugs has been comprehensively reviewed and the interested reader is directed to these references for further details.^25,26 Although incompletely understood, the currently accepted view is that lipids may enhance bioavailability via a number of potential mechanisms, including :

(a) Alterations (reduction) in gastric transit, thereby slowing delivery to the absorption site and increasing the time available for dissolution.²⁷

(b) Increases in effective lumenal drug solubility. The presence of lipids in the GI tract stimulates an increase in the secretion of bile salts (BS) and endogenous biliary lipids including phospholipid (PL) and cholesterol (CH), leading to the formation of BS/PL/CH intestinal mixed micelles and an increase in the solubilisation capacity of the GI tract. However, intercalation of administered (exogenous) lipids into these BS structures either directly (if sufficiently polar), or secondary to digestion, leads to swelling of the micellar structures and a further increase in solubilisation capacity²⁷.

(c) Stimulation of intestinal lymphatic transport. for highly lipophilic drugs, lipids may enhance the extent of lymphatic transport and increase bioavailability directly, or indirectly via a reduction in first-pass metabolism.²⁸

(d) Changes in the biochemical barrier function of the GI tract. It is clear that certain lipids and surfactants may attenuate the activity of intestinal efflux transporters, as indicated by the p-glycoprotein efflux pump, and may also reduce the extent of enterocyte-based metabolism.^29,30

(e)Changes in the physical barrier function of the GI tract. Various combinations of lipids, lipid digestion products and surfactants have been shown to have permeability enhancing properties.^31,32 For the most part, however, passive intestinal permeability is not thought to be a major barrier to the bioavailability of the majority of poorly water-soluble, and in particular, lipophilic drugs.

Enhanced Drug Absorption by Lymphatic Delivery:

Charman et al. proposed that drug candidates for lymphatic transport should have a log P>5 and, in addition, a triglyceride solubility >50 mg/ml. The importance of lipid solubility was illustrated by a comparing the lymphatic transport of DDT (dichlorodiphenyltrichloroethane) (logP 6.19) with hexachlorobenzene\ (HCB, log P 6.53). While both compounds have similar logP values, the difference in lymphatic transport on administration in oleic acid, 33.5% of the dose in the case of DDT and 2.3% with HCB, was attributed to the 13-fold difference in triglyceride solubility³³. However, combination of a high log P and high triglyceride solubility does not always guarantee significant lymphatic transport. Penclomedine, an experimental cytotoxic agent with a log P of 5.48 and a triglyceride solubility of 175 mg/ ml, was poorly transported in the intestinal lymph, ~3% of the dose.²⁵

Absorption of Drugs:

Most of the dietary lipids are triglycerides which are fatty acids ester of glycerol. Generally lipase digests the fat. On ingestion of the triglycerides a course emulsion is believed to form in stomach with dietary phospholipids, proteins and polysaccharides are believed to be potent emulsifiers, forming a monolayer around the triglyceride droplets^34,35 (Figure 1). Around 10 to 40% of normal fat digestion takes place in the stomach, involving hydrolysis to diglycerides and fatty acids This process is being done by human gastric lipase (HGL). Short chain fatty acids may dissolve into the aqueous phase followed by absorption across the stomach mucosa, while longer chain acids may remain incorporated in the emulsion droplet core ^36,37. The emulsion passes to the upper section of the large intestine where particle size reduction of the droplets takes place due to the presence of a range of emulsifying agent including bile salts, monoglycerides, cholesterol, lecithin and lysolecithin, yielding an approximate size range of 0.5 to 1 μm³⁸ (Figure 2).

Fig. 1 Processing of lipids and co-administered drug

The bioavailability enhancement of a drug is generally depends on its dissolution behavior or particle charges of the drug molecule. The drug L-365, 260 was prepared as labrafil M2125 and tween 80 SEDDS preparation³⁹ which showed a seven to eight folds in increase in Cmax compared to a tablet or suspension formulation. The absorption profile for SEDDS were similar to the profile observed after administration of a PEG-600 solution, but the rate limiting step to absorption may be dissolution of the drug in GIT fluid rather than lipid digestion. Shah et al.,⁴⁰ examined the bioavailability of Ro-150778, a highly lipophillic naphthalene derivative, demonstrating a four folds greater bioavailability for SEDD formulation than PEG-400 solution and demonstrative a 20 folds greater bioavailability than from a standard tablet formulation. Here the aspect of drug absorption from SEDD formulation is due to the particle charge (Figure 3).

Fig. 2 Intestinal pre-absorptive processes

Fig. 3 Distribution of drug solubilized in an emulsion.

EVALUATION OF SEDDS:

Thermodynamic stability studies:

The physical stability of a lipid –based formulation is also crucial to its performance, which can be adversely affected by precipitation of the drug in the excipients matrix. In addition, poor formulation physical stability can lead to phase separation of the excipient, affecting nots only formulation performance, but visual appearance as well. In addition, incompatibilities between the formulation and the gelatin capsules shell can lead to brittleness or deformation, delayed disintegration, or incomplete release of drugs.

(1) Heating cooling cycle: Six cycles between refrigerator temperature 40^oC and 45^oC with storage at each temperature of not less than 48 h is studied. Those formulations, which are stable at these temperatures, are subjected to centrifugation test.

(2) Centrifugation: Passed formulations are centrifuged thaw cycles between 21^oC and 25^oC with storage at each temperature for not less than 48 h is done at 3500 rpm for 30 min. Those formulations that does not show any phase separation are taken for the freeze thaw stress test.

(3) Freeze thaw cycle: Three freeze for the formulations. Those formulations passed this test showed good stability with no phase separation, creaming, or cracking.⁴¹

(4) Dispersibility test: The efficiency of self-emulsification of oral nano or micro emulsion is assessed using a standard USP XXII dissolution apparatus 2. One milliliter of each formulation is added to 500 mL of water at 37 ± 0.5 0C. A standard stainless steel dissolution paddle rotating at 50 rpm provided gentle agitation. The in vitro performance of the formulations is visually assessed using the following grading system:

Grade A: Rapidly forming (within 1 min) nanoemulsion, having a clear or bluish appearance.

Grade B: Rapidly forming, slightly less clear emulsion, having a bluish white appearance.

Grade C: Fine milky emulsion that formed within 2 min.

Grade D: Dull, grayish white emulsion having slightly oily appearance that is slow to emulsify (longer than 2min).

Grade E: Formulation, exhibiting either poor or minimal emulsification with large oil globules present on the surface.

Grade A and Grade B formulation will remain as SNEDDS when dispersed in GIT. While formulation falling in Grade C could be recommend for SMEDDS formulation.⁴¹

Turbidimetric Evaluation:

Nepheloturbidimetric evaluation is done to monitor the growth of emulsification. Fixed quantity of Selfemulsifying system is added to fixed quantity of suitable medium (0.1N hydrochloric acid) under continuous stirring (50 rpm) on magnetic plate at ambient temperature, and the increase in turbidity is measured using a turbidimeter. However, since the time required for complete emulsification is too short, it is not possible to monitor the rate of change of turbidity (rate of emulsification).^40,42

Viscosity Determination:

The SEDDS system is generally administered in soft gelatin or hard gelatin capsules. So, it can be easily pourable into capsules and such system should not too thick to create a problem. The rheological properties of the micro emulsion are evaluated by Brookfield viscometer. This viscosities determination conform whether the system is w/o or o/w. If system has low viscosity then it is o/w type of the system and if high viscosities then it is w/o type of the system.^40,42

Droplet Size Analysis Particle Size Measurements:

The droplet size of the emulsions is determined by photon correlation spectroscopy (which analyses the fluctuations in light scattering due to Brownian motion of the particles) using a Zetasizer able to measure sizes between 10 and 5000 nm. Light scattering is monitored at 25°C at a 90° angle, after external standardization with spherical polystyrene beads. The nanometric size range of the particle is retained even after 100 times dilution with water which proves the system’s compatibility with excess water.^40,42

Refractive Index and Percent Transmittance:

Refractive index and percent tranmittance proved the transparency of formulation. The refractive index of the system is measured by refractometer by placing drop of solution on slide and it compare with water (1.333). The percent transmittance of the system is measured at particular wavelength using UV-spectrophotometer keeping distilled water as blank.If refractive index of system is similar to the refractive index of water (1.333) and formulation have percent transmittance > 99 percent, then formulation have transparent nature.

Electro conductivity Study:

The SEDD system contains ionoc or non-ionic surfactant, oil, and water.So, this test is used to measure the electoconductive nature of system. The electroconductivity of resultant system is measured by electoconductometer.

In Vitro Diffusion Study:

In vitro diffusion studies is performed to study the release behavior of formulation from liquid crystalline phase around the droplet using dialysis technique.⁴⁰

Drug content:

Drug from pre-weighed SEDDS is extracted by dissolving in suitable solvent. Drug content in the solvent extract is analyzed by suitable analytical method against the standard solvent solution of drug.

APPLICATIONS:

Improvement in Solubility and bioavailability: If drug is incorporated in SEDDS, it increases the solubility because it circumvents the dissolution step in case of Class-П drug (Low solubility/high permeability). Ketoprofen, a moderately hydrophobic (logP 0.979) nonsteroidal anti-inflammatory drug (NSAID), is a drug of choice for sustained release formulation has high potential for gastric irritation during chronic therapy. Also because of its low solubility, ketoprofen shows incomplete release from sustained release formulations. Vergote et al. (2001) reported complete drug release from sustained release formulations containing ketoprofen in nanocrystalline form.⁴³Different formulation approaches that have been sought to achieve sustained release, increase the bioavailability, and decrease the gastric irritation of ketoprofen include preparation of matrix pellets of nano-crystalline ketoprofen,⁴³ sustained release ketoprofen microparticles and formulations,⁴⁴ floating oral ketoprofen systems,⁴⁵ and transdermal systems of ketoprofen.^[46] Preparation and stabilization of nano-crystalline or improved solubility forms of drug may pose processing, stability, and economic problems. This problem can be successfully overcome when Ketoprofen is presented in SEDDS formulation. This formulation enhanced bioavilability due to increase the solubility of drug and minimizes the gastric irritation. Also incorporation of gelling agent in SEDDS sustained the release of Ketoprofen. In SEDDS, the lipid matrix interacts readily with water,forming a fine particulate oil-in-water (o/w) emulsion. The emulsion droplets will deliver the drug to the gastrointestinal mucosa in the dissolved state readily accessible for absorption. Therefore, increase in AUC i.e. bioavailability and Cmax is observed with many drugs when presented in SEDDS.

MODIFICTION OF SEDDS:

Supersaturable SEDDS (S-SEDDS):

The high surfactant level typically present in SEDDS formulations can lead to GI side-effects and a new class of supersaturable formulations, including supersaturable SEDDS . (S-SEDDS) formulations, have been designed and developed to reduce the surfactant side-effects and achieve rapid absorption of poorly soluble drugs.^47,49 The S-SEDDS approach is to generate a protracted supersaturated solution of the drug when the formulation is released from an appropriate dosage form into an aqueous medium. Surpersaturation is intended to increase the thermodynamic activity to the drug beyond its solubility limit and, therefore, to result in an increased driving force for transit into and across the biological barrier.⁴⁹ The S-SEDDS formulations contain a reduced level of surfactant and a polymeric precipitation inhibitor to yield and stabilize a drug in a temporarily supersaturated state. Hydroxypropyl methyliquid crystalellulose (HPMC) and related cellulose polymers are well recognized for their propensity to inhibit crystallization and, thereby, generate and maintain the supersaturated state for prolonged time periods.^50,55

Supersaturable self-emulsifying drug delivery system (S-SEDDS):

S-SEDDS of paclitaxel was developed employing HPMC as a precipitation inhibitor with a conventional SEDDS formulation. In vitro dilution of the S-SEDDS formulation results in formation of a microemulsion, followed by slow crystallization of paclitaxel on standing. This result indicates that the system is supersaturated with respect to crystalline paclitaxel, and the supersaturated state is prolonged by HPMC in the formulation. In the absence of HPMC, theSEDDS formulation undergoes rapid precipitation, yielding a low paclitaxel solution concentration. A pharmacokinetic study showed that the paclitaxel S-SEDDS formulation produces approximately a 10-fold higher maximum concentration (Cmax) and a 5-fold higher oral bioavailability (F 9.5%) compared with that of the orally administered Taxol formulation (F 2.0%) and the SEDDS formulation without HPMC (F1%).⁴⁹

DOSAGE FORM DEVELOPMENT OF S-SEDDS:

SEDDS are normally prepared as liquid dosage forms that can be administrated in soft gelatine capsules, which have some disadvantages especially in the manufacturing process. An alternative method is the incorporation of liquid self-emulsifying ingredients into a powder in order to create a solid dosage form (tablets, capsules).

Dry emulsions (Solid SEDDS):

Dry emulsions are powders from which emulsion spontaneously occurs in vivo or when exposed to an aqueous solution. Dry emulsions can be useful for further preparation of tablets and capsules. Dry emulsion formulations are typically prepared from oil/ water (O/W) emulsions containing a solid carrier (lactose, maltodextrin, and so on) in the aqueous phase by rotary evaporation,⁵⁶ freeze-drying⁵⁷or spray drying.^58–60Myers and Shively obtained solid state glass emulsions in the form of dry ‘foam’ by rotary evaporation, with heavy mineral oil and sucrose. Such emulsifiable glasses have the advantage of not requiring surfactant⁹¹. In freeze-drying, a slow cooling rate and the addition of amorphous cryoprotectants have the best stabilizing effects, while heat treatment before thawing decreases the stabilizing effects.⁵⁷ The technique of spray drying is more frequently used in preparation of dry emulsions. The O/W emulsion was formulated and then spray-dried to remove the aqueous phase. The most exciting finding in this field ought to be the newly developed enteric-coated dry emulsion formulation, which is potentially applicable for the oral delivery of peptide and protein drugs. This formulation consisted of a surfactant, a vegetable oil, and a pH-responsive polymer, with lyophilization used.⁶¹ Recently, Cui et al. prepared dry emulsions by spreading liquid O/W emulsions on a flat glass, then dried and triturated to powders.⁶²

Self-emulsifying capsules:

After administration of capsules containing conventional liquid SE formulations, microemulsion droplets form and subsequently disperse in the GI tract to reach sites of absorption. However, if irreversible phase separation of the microemulsion occurs, an improvement of drug absorption cannot be expected. For handling this problem, sodium dodecyl sulfate was added into the SE formulation.⁶³

Supersaturable SEDDS:

With the similar purpose, the supersaturatable SEDDS was designed, using a small quantity of HPMC (or other polymers) in the formulation to prevent precipitation of the drug by generating and maintaining a supersaturated state in vivo. This system contains a reduced amount of a surfactant, thereby minimizing GI side effects.^62,64

Besides liquid filling, liquid SE ingredients also can be filled into capsules in a solid or semisolid state obtained by adding solid carriers (adsorbents, polymers, and so on). As an example, a solid PEG matrix can be chosen. The presence of solid PEG neither interfered with the solubility of the drug, nor did it interfere with the process of self-nanoemulsification upon mixing with water.^65,66

Self-emulsifying sustained/controlled-release tablets:

Combinations of lipids and surfactants have presented great potential of preparing SE tablets that have been widely researched. Nazzal and Khan evaluated the effect of some processing parameters (colloidal silicates—X1, magnesium stearate mixing time— X2, and compression force—X3) on hardness and coenzymum Q10 (CoQ10) dissolution from tablets of eutectic-based SMEDDS. The optimized conditions (X1 = 1.06%, X2 = 2 min, X3 = 1670 kg) were achieved by a face-centered cubic design.⁶⁷ In order to reduce significantly the amount of solidifying excipients required for transformation of SEDDS into solid dosage forms, a gelled SEDDS has been developed by Patil et al. In their study, colloidal silicon dioxide (Aerosil 200) was selected as a gelling agent for the oil-based systems, which served the dual purpose of reducing the amount of required solidifying excipients and aiding in slowing down of the drug release.⁶⁸

Self-emulsifying sustained/controlled-release pellets:

Pellets, as a multiple unit dosage form, possess many advantages over conventional solid dosage forms, such as flexibility of manufacture, reducing intrasubject and intersubject variability of plasma profiles and minimizing GI irritation without lowering drug bioavailability.^[69] Thus, it is very appealing to combine the advantages of pellets with those of SEDDS by SE pellets. Serratoni et al. prepared SE controlled-release pellets by incorporating drugs into SES that enhanced their rate of release, and then by coating pellets with a water-insoluble polymer that reduced the rate of drug release. Pellets were prepared by extrusion/ spheronization and contained two water-insoluble model drugs (methyl and propyl parabens); SES contained mono-diglycerides and Polysorbate 80. As shown in Figure 1, this research demonstrated that combinations of coating and SES could control in vitro drug release by providing a range of release rates; and the presence of the SEDDS did not influence the ability of the polymer film to control drug dissolution⁷⁰. There is another report that SE sustained-release matrix pellets could be successfully formulated with glyceryl palmito-stearate (Gelucire 54/02) and glyceryl behenate (Gelucire 70/02).⁷¹

Self-emulsifying solid dispersions:

Although solid dispersions could increase the dissolution rate and bioavailability of poorly water-soluble drugs, some manufacturing difficulties and stability problems existed. Serajuddin pointed out that these difficulties could be surmounted by the use of SE excipients.^72,73 These excipients have the potential to increase further the absorption of poorly water-soluble drugs relative to previously used PEG solid dispersions and may also be filled directly into hard gelatin capsules in the molten state, thus obviating the former requirement for milling and blending before filling.⁷¹ SE excipients like Gelucire1 44/14, Gelucire1 50/02, Labrasol1, Transcutol1 and TPGS (tocopheryl polyethylene glycol 1000 succinate) have been widely used in this field.^69-72

Self-emulsifying beads:

In an attempt to transform SES into a solid form with minimum amounts of solidifying excipients, Patil and Paradkar investigatedloading SES into the microchannels of porous polystyrene beads (PPB) using the solvent evaporation method. PPB with complex internal void structures are typically produced by copolymerizing styrene and divinyl benzene. They are inert, stable over a wide pH range and to extreme conditions of temperature and humidity. This research concluded that PPB were potential carriers for solidification of SES, with sufficiently high SES to PPB ratios required to obtain solid form. Geometrical features, such as bead size and pore architecture of PPB, were found to govern the loading efficiency and in vitro drug release from SES-loaded PPB .

Self-emulsifying nanoparticles:

Nanoparticle techniques have been useful in the production of SE nanoparticles. Solvent injection is one of these techniques. In this method, the lipid, surfactant, and drugs were melted together, and injected drop wise into a stirred non-solvent. The resulting SE nanoparticles were thereafter filtered out and dried. This approach yielded nanoparticles (about 100 nm) with a high drug loading efficiency of 74%. A second technique is that of sonication emulsion–diffusion–evaporation, by which co-loading 5-fluorouracil (5-FU) and antisense EGFR (epidermal growth factor receptor) plasmids in biodegradable PLGA/O-CMC nanoparticles was realized. The mixture of PLGA (poly-lactide-co-glycolide) and O-CMC (O-carboxmethyl-chitosan) had a SE effect, with no need to add another surfactant stabilizer. Eventually the 5-FU and plasmid encapsulation efficiencies were as high as 94.5% and 95.7%, respectively, and the 5-FU release activity from such nanoparticles could be sustained for as long as three weeks ^[74]. More recently, Trickler et al. developed a novel nanoparticle drug delivery system consisting of chitosan and glyceryl monooleate (GMO) for the delivery of paclitaxel (PTX). These chitosan/ GMO nanoparticles, with bioadhesive properties and increased cellular association, were prepared by multiple emulsion (o/w/o) solvent evaporation methods. The SE property of GMO enhanced the solubility of PTX and provided a foundation for chitosan aggregation, meanwhile causing near 100% loading and entrapment efficiencies of PTX. These advantages allow the use of lower doses of PTX to achieve an efficacious therapeutic window, thus minimizing the adverse side effects associated with chemotherapeutics like PTX.⁷⁵ Self-emulsifying suppositories Some investigators proved that S-SEDDS could increase not only GI adsorption but also rectal/vaginal adsorption.⁷⁶ Glycyrrhizin, which, by the oral route, barely achieves therapeutic plasma concentrations, can obtain satisfactory therapeutic levels for chronic hepatic diseases by either vaginal or rectal SE suppositories. The formulation included glycyrrhizin and a mixture of a C6–C18 fatty acid glycerol ester and a C6–C18 fatty acid macrogol ester.⁷⁷ Self-emulsifying implants Research into SE implants has greatly enhanced the utility and application of S-SEDDS. As an example, 1,3-bis(2-chloroethyl)-1- nitrosourea (carmustine, BCNU) is a chemotherapeutic agent used to treat malignant brain tumors.

CONCLUSION:

As mentioned above, numerous studies have confirmed that SSEDDS substantially improved solubility/dissolution, absorption and bioavailability of poorly water-soluble drugs. As improvements or alternatives of conventional liquid SEDDS, S-SEDDS are superior in reducing production cost, simplifying industrial manufacture, and improving stability as well as patient compliance. Most importantly, S-SEDDS are very flexible to develop various solid dosage forms for oral and parenteral administration. Moreover, GI irritation is avoidable and controlled/sustained release of drug is achievable.

There is still a long way to go, however, before more solid SE dosage forms (except for SE capsules) appear on the market. Because there exist some fields of S-SEDDS to be further exploited, such as studies about human bioavailability and correlation of in vitro/in vivo. Moreover, the researches of S-SEDDS lose their balance, that is, SE implants/suppositories/microspheres have not been as extensively studied as SE tablets/pellets/capsules. It is also worth pointing out some issues to which much attention should be paid, for example physical aging phenomenon associated with glyceride, oxidation of vegetable oil,⁷⁸ and interaction between drugs and excipients. Selection of suitable excipients is the main hurdle of developing S-SEDDS.⁷⁹ Thus, these aspects should represent the major future working directions for S-SEDDS.

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Received on 19.01.2010

Accepted on 17.02.2010

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(3): May-June 2010, 206-214